Epithelial Junction Opener JO-1 Improves Monoclonal Antibody Therapy of Cancer

Abstract

The efficacy of monoclonal antibodies (mAbs) used to treat solid tumors is limited by intercellular junctions which tightly link epithelial tumor cells to each another. In this study, we define a small, recombinant adenovirus serotype 3-derived protein, termed junction opener 1 (JO-1), which binds to the epithelial junction protein desmoglein 2 (DSG2). In mouse xenograft models employing Her2/neu- and EGFR-positive human cancer cell lines, JO-1 mediated cleavage of DSG2 dimers and activated intracellular signaling pathways which reduced E-cadherin expression in tight junctions. Notably, JO-1-triggered changes allowed for increased intratumoral penetration of the anti-Her2/neu mAb trastuzumab (Herceptin) as well as improved access to its target receptor, Her2/neu, which is partly trapped in tight junctions. This effect translated directly into increased therapeutic efficacy of trastuzumab in mouse xenograft models using breast, gastric, and ovarian cancer cells that were Her2/neu-positive. Furthermore, combining JO-1 with the EGFR-targeting mAb cetuximab (Erbitux) greatly improved therapeutic outcomes in a metastatic model of EGFR-positive lung cancer. Taken together, our findings offer preclinical proof of concept to employ JO-1 in combination treatments which enhance the efficacy of trastuzumab treatment, by generating a transient degradation of tumor stroma proteins that can elicit eradication of tumors.

Enhancement of the Tumor Penetration of Monoclonal Antibody by Fusion of a Neuropilin-Targeting Peptide Improves the Antitumor Efficacy

“…This is similar to that observed with the coadministration of JO-1 viral protein and cetuximab or trastuzumab (10). In the epithelial-mesenchymal transition, tumor cells typically lose the epithelial marker E-cadherin and gain mesenchymal markers, such as vimentin and N-cadherin (35,36).…”

“…These properties were directly linked to their superior antitumor efficacy in mouse xenograft models over that of the parent mAbs. Coadministration of mAbs with promoter agents was previously shown to augment the vascular permeability and/or penetration within tumor tissues, which significantly improved the in vivo antitumor efficacy (8,10). However, our approach of directly fusing a tumor-homing and tissue-penetrating peptide to solid tumor-targeting mAbs has not been previously reported.…”

“…For example, coadministration of an internalizing Arg-Gly-Asp (iRGD) tumor-penetrating peptide (7)(8)(9) and a viral protein called epithelial junction opener-1 (JO-1; ref. 10) significantly enhanced tumor penetration and antitumor efficacy of the anti-Her2 mAb trastuzumab (Herceptin) and the anti-EGF receptor (EGFR) mAb cetuximab (Erbitux), respectively, in mouse xenograft tumor models.…”

Towards Sustained Silencing of HER2/neu in Cancer By Epigenetic Editing

“…Alternatively, tight attachment of epithelial cancer cells via upregulation of epithelial proteins in the intercellular junctions can result in the escape of the Her2/neu receptor from trastuzumab and other receptor-targeted therapies. Indeed, loosening the tight lateral junctions increased the surface presence of the Her2/neu receptor in vitro and in vivo, subsequently improving trastuzumab efficiency (13).…”

Intracellular Signaling and Desmoglein 2 Shedding Triggered by Human Adenoviruses Ad3, Ad14, and Ad14P1

“…JO1 can be purified by affinity chromatography. We are currently developing JO1 derivatives for clinical applications to increase the penetration of chemotherapy drugs in epithelial tumors (34)(35)(36).…”